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Studies on orally active antidiabetic vanadium complexes with low toxicity and long-term action

低毒长效口服抗糖尿病钒配合物的研究

基本信息

批准号：
08457622
负责人：
SAKURAI Hiromu
金额：
$ 4.67万
依托单位：
Kyoto Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457622/
关键词：
vanadium vanadyl complex diabetes insulin-like action nitric oxide IDDM NIDDM

项目摘要

We studied on development of orally active antidiabetic vanadyl complexes with low toxicity and long-term action to know the structure of the complex-activity relationship. Research was performed in the following steps. (1) Preparation of vanadyl complexes with different coordination modes and analysis of the structure. (2) In vitro evaluation of the complex using rat adipocytes in terms of suppression of free fatty acids and (3) in vivo evaluation of the possible complex, which was given to streptozotocin (STZ)-induced insulin-dependent diabetes mellitus (IDDM) rats or none-insulin-dependent diabetes mellitus (NIDDM) mice by ip injection or oral administration.From the results for 2 years, we found that a vanadyl-picolinate complex with vo (v_2o_2) coordination mode has a good blood glucose normalizing effect on oral administration. Then we extended our work to find better complexes and found vanadyl-6-methyl-picolinate complex with low toxicity and long-term action when administered orally. The action mechanism of the complex was also analyzed in terms of vanadium organ distribution and pharmacokinetics. Interestingly, the complex was found to be effective on NIDDM mice when given by ip injection or oral administration. On the other hand, vanadium was found to be effective on the protection of development of STZ-induced diabetes. On the basis of the results, vanadium compounds were found to be effective to treat both IDDM and NIDDM in experimental animals as well as to protect the development of IDDM.

本课题研究开发具有长期作用、低毒的口服降糖活性钒氧配合物，以了解配合物的结构与活性的关系。研究按以下步骤进行。(1)不同配位模式钒配合物的制备及结构分析。(2)使用大鼠脂肪细胞在抑制游离脂肪酸方面对复合物进行体外评价，以及（3）通过ip注射或口服给药给链脲佐菌素（STZ）诱导的胰岛素依赖型糖尿病（IDDM）大鼠或非胰岛素依赖型糖尿病（NIDDM）小鼠的可能复合物的体内评价。我们发现具有VO（V_2O_2）配位模式的吡啶甲酸氧钒络合物对口服给药具有良好的血糖正常化作用。在此基础上，我们进一步研究了6-甲基吡啶甲酸氧钒配合物，发现其毒性低，口服作用时间长。并从钒的器官分布和药动学角度分析了配合物的作用机理。有趣的是，当通过ip注射或口服给药时，发现该复合物对NIDDM小鼠有效。另一方面，发现钒对STZ诱导的糖尿病的发展具有保护作用。结果表明，钒化合物对实验动物的IDDM和NIDDM均有治疗作用，并对IDDM的发展有保护作用。